Interleukin-13 (IL-13) is involved in the induction of IgE and IgG4 production, as well as the differentiation of T-helper (Th) cells into a secretory (Th2) phenotype. These immunostimulatory steps are critical in the development of atopic diseases which are a major threat to human health, such as anaphylaxis (Howard et al, Am J Hum Genet 70(1):230-236, 2002; Noguchi et al, Hum Immunol 62(11):1251-1257, 2001), as well as milder conditions such as hay fever, allergic rhinitis and chronic sinusitis which, although not life-threatening, are responsible for considerable morbidity worldwide.
IL-13 is a mediator in the pathology of the acute and chronic stages of asthma. During an asthma attack, its expression increases and its effects include reduction of the capacity of lung epithelial cells to maintain a tight barrier against inhaled particles and pathogens (Ahdieh et al, Am J. Physiol. Cell Physiol. 281(6):C2029-2038, 2000) and promotion of allergen-induced airway hyper-responsiveness (Morse et al, Am. J. Physiol. Lung Cell Mol. Physiol. 282(1):L44-49, 2002). In the longer term, IL-13 promotes non-inflammatory structural changes to asthmatic airways, such as enhanced expression of mucin genes, airway damage and obstruction of the small airways (Howard et al, 2002, supra; Danahay et al, Am. J. Physiol. Lung Cell Mol. Physiol. 282(2):L226-236, 2002).
The biological effects of IL-13 are mediated by a dimeric receptor complex including the subunits IL-13Rα1 and IL-4Rα. It is postulated that IL-13 binding to IL-13Rα1 triggers dimerization with IL-4Rα and activation of intracellular mediators that include the Janus Kinases JAK1 and JAK2, as well as STAT6, ERK and p38 (David et al, Oncogene 20(46):6660-6668, 2001; Perez et al, J. Immunol. 168(3):1428-1434, 2002).
IL-13 shows many overlapping biological effects with those of IL-4. IL-13 and IL-4 are related by sequence and are involved in many related processes, such as myelopoiesis and the regulation of monocyte/macrophage pro-inflammatory functions. For example, both IL-13 and IL-4 have been shown to effect B cells in a similar fashion, up-regulating surface molecules such as MHC class II and CD23 molecules, and promoting the secretion of IgG4 and IgE.
The overlapping activities of IL-13 and IL-4 can be explained in part by their shared dimeric receptor complex. The IL-13 receptor complex is composed of an IL-13Rα1 and an IL-4Rα; this same receptor complex is also the Type II IL-4 receptor complex (Callard et al, Immunology Today 17(3):108, 1996). As such, in looking to achieve therapeutic control of the IL-13 receptor complex by blocking cytokine-mediated signaling, it may be useful to have not only a molecule that inhibits signaling mediated by IL-13, but a molecule that inhibits signaling mediated by both IL-13 and IL-4.
Gauchat et al (Eur. J. Immunol. 28:4286-4298, 1998) reported murine antibodies to human IL-13Rα1 which blocked interaction of a tagged IL-13 with a tagged and immobilized soluble IL-13Rα1. These antibodies also inhibited IL-13 binding to IL-13Rα1 in transfected HEK-293 cells. However, all of these antibodies failed to neutralize IL-13-induced biological activity, suggesting that they were not antagonists of the complete IL-13Rα1/IL-4Rα receptor complex. In a later paper, Gauchat et al (Eur. J. Immunol. 30:3157-3164, 2000) reported a rat antibody, designated as C41, to murine IL-13Rα1 which bound to HEK-293 cells transfected with murine IL-13Rα1. However, C41 did not neutralize IL-13-induced biological activities. Further, C41 did not react with the soluble form of human IL-13Rα1. Akaiwa et al (Cytokine 13:75-84, 2001) reported an antibody that recognized soluble IL-13Rα1 by enzyme immunoassay and a tagged full-length IL-13Rα1 transfected into COS7 cells. The antibody was used for immunohistochemistry but there is no indication that it was a neutralizing antibody.
WO 03/46009 teaches murine antibodies to human IL-13Rα1 which inhibited TF-1 cell response to IL-13 but not to IL-4, and Krause et al (Mol Immunol. 43(11):1799-807, 2006) describe murine antibodies to human IL-13Rα1 which inhibit IL-13-dependant TF-1 cell proliferation. Antibodies to hIL-13Rα1 are also known from WO 97/15663, WO 03/080675, WO 06/072564 and Vermot-Desroches et al., 2000 Tissue Antigens 5(Supp. 1):52-53 (Meeting Abstract).
Despite these reports, there remains a need for antibodies to human IL-13Rα1 that are suitable for administration to humans and that block IL-13 activity.